Alcoholism and opiate addiction lead to major health-related problems and societal costs for people in the United States and the rest of the world as well. Therefore, research and development for improved pharmacologic treatments for drug and alcohol abuse are very important. Naltrexone, an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently, naltrexone has been indicated as an adjunct in the treatment of alcohol dependence, as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing prodrugs, which are more skin permeable than naltrexone, in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone and prodrugs in combination with microneedle treatment will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools for investigating quantitative structure-permeability relationships (QSPR) for transdermal flux and optimization of flux in combination with microneedle enhancement. These prodrugs/microneedles should improve naltrexone delivery rates across the skin because of optimized physicochemical properties for faster diffusion. The specific aims of this project include: (1) to synthesize a series of naltrexone and naltrexol (active metabolite) prodrugs designed to elucidate fundamental QSPRs for transdermal flux optimization with and without microneedle use, (2) to characterize the physicochemical parameters of the drugs, including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the drugs'penetration and concurrent bioconversion through human skin in vitro with and without microneedle use, and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with and without microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPR database for transdermal prodrugs with and without microneedle use, as well as help to identify the most promising prodrug/microneedle system for eventual human use.